Aging and age-related degenerative disease has received increased attention due to its socioeconomic impact in the western world. Even though there are significant gender differences in age-related diseases such as AD, we still do not know which internal or external factors regulate this process. AD is signified by a marked loss of forebrain cholinergic neurons, and this disease occurs more often in women than men. Incorrect processing of amyloid precursor protein (APP) may play a significant role in AD, and the high incidence of AD in elderly women could depend on menopause and a lack of estrogen in the brain. Recent evidence from tissue culture experiments suggests a multifactorial process, and a relationship between APP, steroid hormones and NGF. However, no in vivo models have been designed to explore this relationship. Ts65Dn mice with segmental trisomy of Chr 16 (including the APP gene) have an overexpression of APP, loss of cholinergic forebrain neurons, and cognitive impairment that occurs around 6 months of age. A shorter Chr 16 trisomy, Ts1Cje (excluding the APP gene) lacks cognitive impairment and cholinergic loss. The Ts65Dn mouse can thus be used as a model for accelerated aging and neurodegeneration, to test the hypothesis that APP, estrogen and NGF interact to maintain the cholinergic system. Using a problem-based approach to study degeneration, the lab has used an aged rat model over the past five years to study a new, noninvasive delivery system for NGF. This delivery system will now be used to study memory loss and cholinergic degeneration in Ts65Dn mice. The specific aims are: 1) is there an alteration in APP processing and/or alterations in NGF levels in forebrain or hippocampus during the time of cholinergic cell loss in Ts65Dn mice? 2) Do ovariectomy and estrogen replacement therapy alter cognitive impairment, cholinergic degeneration and/or NGF/APP levels? 3) Do transplants of wildtype cholinergic neurons succumb to the same phenotype loss when grafted into a TS65DN host? And 4) Can treatment with NGF and/or estrogen alleviate cognitive alterations and cholinergic phenotype loss in the Ts65Dn mouse?